As early as 1983, human immunodeficiency virus type-1 (HIV-1) infection and the various disease states caused by the virus (e.g., AIDS and ARC) were recognized in pediatric patients (Oleske et al. (1983) J. Am. Med. Assoc. 249: 2345-2349; Rubinstein et al. (1983) J. Am. Med. Assoc. 249: 2350-2356). In Europe and North America, infants account for a small but increasing portion of the new cases of HIV-1 infection (Scott et al. (1984) NE J. Med. 310: 76-81; Piot et al. (1988) Science 239: 573-579; Curran et al. (1988) Science 239: 610-616). However, due to lack of proper education and training of parents and adequate preventative measures, these numbers will soon increase drastically. In Central and East Africa, nearly 10% of all parturient women are seropositive. With an overall transmission rate of 30%, approximately 3% of all infants born in this part of Africa are expected to be infected (Ryder et al. (1989) NE J. Med. 320: 1637-1642). A recent report from the Centers for Disease Control indicates that cases associated with heterosexual HIV-1 transmission have been increasing steadily in the United States since 1986 (Centers for Disease Control (1991) Morbid. Mortal. Weekly Rep. 40: 357-358). New cases have occurred more frequently among women than men, and the rate of perinatal HIV-1 transmission in children has continued to increase (Centers for Disease Control (1991) Morbid. Mortal. Weekly Rep. 40: 357-358). These statistics call for an immediate search for effective methods to prevent establishment of fetal or newborn HIV-1 infection.
To test different therapeutic and prophylactic strategies and vaccines, an animal model of the course of HIV-1, or other lentiviral, fetal infection is important. Murine models to study transplacental or perinatal antiretroviral therapy are known (Sharpe et al. (1987) Science 236: 1671-1674; Sharpe et al. (1988) Proc. Natl. Acad. Sci. (USA) 85: 9792-9796; Sharpe et al. (1989) J. Virol. 63: 1049-1053). While experiments in these models yielded promising results, the existing murine models involve Type C retroviruses which lack the regulatory genes present in lentiviruses and differ significantly in their pathobiology from HIV-1. In addition, mammalian models utilizing rhesus monkeys have been established to study the course of non-retroviral fetal infection by simian cytomegalovirus, Venezuelan and Western equine encephalitis virus, and mumps virus (London et al. (1986) Teratology 33: 323-331; London et al. (1977) Teratology 16: 285-296; London et al. (1982) Teratology 25: 71-79; London et al. (1979) J. Inf. Diseases 139: 324-328).
Infection of rhesus monkeys (Macaca mulatta) with simian immunodeficiency virus (SIV) closely mimics HIV-1 infection in humans. Both HIV-1 and SIV are lentiviruses with similar molecular architecture (Chakrabarti et al. (1987) Nature 328: 543-547), and both cause immunodeficiency resulting in opportunistic infections as well as central nervous system damage (Letvin et al. (1985) Science 230: 71-73). However, in utero transmission of SIV in rhesus monkeys has not been well established. In one documented case, three infants were born SIV-infected in a captive macaque colony (Daniel et al. (1988) Int. J. Cancer 41: 601-608). Two more cases have been reported involving other species of monkeys (Eichberg et al. (1988) NE J. Med. 319: 722-723; Jehuda-Cohen et al. (1991), J. AIDS 4: 204-205). In one, a pregnant chimpanzee, inoculated intravenously with 100 50% tissue culture infectious doses (TCID.sub.50) of HIV-1, gave birth to an HIV-1-infected infant which did not develop any sign of disease (Eichberg et al. (1988) NE J. Med. 319: 722-723). Recently, in a separate study, three infants (ages 26, 19 and 9 months) born to sooty mangabey monkeys, naturally infected with a simian immunodeficiency (SIV/smm) virus, were shown to have high levels of SIV-reactive antibodies and virus could be isolated from their peripheral blood mononuclear cells by cocultivation (Jehuda-Cohen et al. (1991), J. AIDS 4: 204-205). It was believed that the transmission of virus may have not occurred through scratches and bites, since most infants remain seronegative after such incidences (Jehuda-Cohen et al. (1991), J. AIDS 4: 204-205). However, proof for maternal transmission is lacking, and these isolated cases have not been reproducible.
When groups of five pregnant rhesus monkeys were injected with SIV in the first, second, or third trimesters respectively, none of the infants born to these mothers was virus positive (Fultz, data presented at the Gallo laboratory meeting, August, 1990.)
Recent developments suggest that pigtailed macaque monkeys (Macaca nemestrina) can be infected with HIV-1 and may provide researchers with a better animal model to study HIV-1 infection (Palca, (1992) Science 256: 1630-1632; Agy et al. (1992) Science, in press; Journal of NIH Research (1992) 4: 42). In addition to being less expensive and more abundant, pigtailed macaques develop viremia and signs of illness, e.g., fever and lymphadenopathy, soon after being infected and will be important as a model in studying the early course of HIV-1 infection.